Minimise Early Relapse in Postmenopausal Hormone-sensitive Breast Cancer

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NON-THEMATIC REVIEW

Minimizing early relapse and maximizing treatment

outcomes in hormone-sensitive postmenopausal breast

cancer: efficacy review of AI trials

Christos J. Markopoulos

Published online: 10 September 2010# The Author(s) 2010. This article is published with open access at Springerlink.com

Abstract Breast cancer is one of the leading causes of

cancer-related deaths in women. Regardless of prognosis,all women with breast cancer are at risk for early

recurrence. Nearly 50% of early recurrences occur within

5 years of surgery, and they peak at 2 years after surgery in

women treated with adjuvant tamoxifen. Most early

recurrences are distant metastases, which strongly correlate

with increased mortality. Treatments that mitigate the risk

of early distant metastases (DM) are, therefore, likely to

improve overall survival in women with early breast cancer

(EBC). Aromatase inhibitors (AIs) — anastrozole, letrozole,

and exemestane — have been investigated as alternatives to

tamoxifen for adjuvant treatment of hormone receptor-

positive (HR+) EBC in postmenopausal women (PMW).

AIs are better at minimizing risk of early relapse compared

with tamoxifen. However, it is not clear if preferential use

of AIs over tamoxifen will benefit all PMW with HR+

EBC. The ability to subtype HR+ breast cancer on the basis

of biomarkers predictive of response to AIs and tamoxifen

would likely be key to determining the most beneficial

hormonal treatment within patient subpopulations, but this

process requires thorough investigation. Until then, adju-

vant therapies that provide the greatest reduction in risk of

DM should be considered for all PMW with HR+ EBC.

This article reviews the clinical trials of AI adjuvant

therapies for hormone-sensitive breast cancer, particularly

in the context of how they compare with tamoxifen in

minimizing the risk of relapse, occurrence of DM, and

breast cancer-related deaths.

Keywords Aromatase inhibitors . Distant metastasis .

Anastrozole . Letrozole . Exemestane . Tamoxifen

1 Introduction

Breast cancer is the most frequently diagnosed cancer in

women and the second leading cause of cancer-related

death in women. In the USA alone, an estimated 192,370

new cases of invasive breast cancer with roughly 40,170

breast cancer deaths were expected to occur in 2009 [1].

Over two thirds of breast cancers are hormone-sensitive and

thus candidates for endocrine therapy. Endocrine therapy

removes estrogen from the body or inhibits estrogen from

binding to cancer cells and is the principal adjuvant

treatment given to postmenopausal women (PMW) with

hormone receptor-positive (HR+) early breast cancer (EBC)

in an attempt to minimize the risk of relapse. The risk of

relapse, which is greatest during the first 5 years of surgery,

peaks at approximately 2 years [2 – 4]. At this peak, distant

metastases (DM) are the most common type of recurrence,

compared with locoregional or contralateral recurrences

[4, 5].

DM comprise between 50% and 75% of all early

recurrences [3, 5, 6], and their appearance is the harbinger

of breast cancer-related death. The 5-year survival rate for

patients with DM is much lower than for patients with

locoregional, contralateral, and no recurrence [5]. There-

fore, reducing the risk of DM is an important therapeutic

goal [5, 7 – 10]. Adjuvant endocrine therapies that are most

effective in reducing the risk of DM may have the most

favorable impact on survival in PMW with EBC. For over

C. J. Markopoulos (*)

Athens University Medical School,

8, Iassiou str,

11521 Athens, Greece

e-mail: [email protected]

C.J. Markopoulos

e-mail: [email protected]

Cancer Metastasis Rev (2010) 29:581 – 594

DOI 10.1007/s10555-010-9248-x



two decades, tamoxifen was thought to be the optimal

adjuvant therapy for PMW with HR+ EBC. Recent studies

have challenged that notion, leading to the consideration of

the aromatase inhibitors (AIs) anastrozole, letrozole, and

exemestane as alternatives to tamoxifen [11 – 16].

Until recently, the use of upfront monotherapy with an

AI (i.e., instead of tamoxifen) versus a sequential/switch

strategy (i.e., after some period of initial tamoxifen) was a matter of considerable debate. However, the importance of

upfront AI therapy is now widely recognized, particularly

in patients at higher risk of early relapse [17]. Indeed,

recent data from the Breast International Group (BIG) 1-98

trial comparing a sequential strategy with tamoxifen

followed by an AI (letrozole) with AI monotherapy has

demonstrated that sequencing is not superior to monother-

apy with an AI (letrozole) alone [16]. Major clinical trials

of adjuvant therapies for hormone-sensitive breast cancer,

which compare the efficacy and safety of AIs with that of

tamoxifen in minimizing the risk of recurrence, DM, and

breast cancer-related deaths, are discussed below.

2 Risk of early relapse and distant metastasis

All patients with breast cancer are at risk for early relapse.

The risk of recurrence is greatest during the first few years

following surgery [2 – 4, 6]. In a recent retrospective

analysis of 3,614 PMW with estrogen receptor-positive

(ER+) EBC who were treated with tamoxifen following

surgery, the annual recurrence rate overall was 4.3%, and

most of these (3.4%) were DM [4] (Fig. 1). Locoregional

and contralateral recurrences did not exceed 1% at any time

during the study. During the 5-year median follow-up of

this patient cohort, 476 developed recurrences, and of these,

344 were DM. Patients with DM had the poorest outcomes:

50% died within 0.65 years (7.8 months) from the time of

DM and 75.6% (260/344) died overall [8]. Lamerato et al.

have consistently reported DM to be the most common site

of recurrence (58.3%), with only 26.1% of recurrences

locoregional, and 15.6% contralateral [5]. The 5-year

probability of overall survival (OS) was poorest for women

with DM (41.3%) compared with those with locoregional

(59.3%), contralateral (83.4%), or no recurrence (91.7%)

[5].

Factors predictive of early recurrence include hormone

receptor (ER and/or progesterone receptor (PgR)) status,

degree of nodal involvement, and tumor size and tumor grade [4, 6, 18]. Patients who have tumors involving >3

nodes, tumors >5 cm, or grade III tumors and who are

receiving adjuvant tamoxifen have about a three-fold

increase in risk of recurrence (all P <0.001) [4]. However,

individual risk factors such as node-negative (N−) status

must be considered along with other factors. For example,

according to the St. Gallen risk classification, patients with

N− tumors that are large (>2 cm), high-grade (histologic

and/or nuclear grades 2 and 3), or show evidence of

peritumoral vascular invasion are considered intermediate

risk [19]. It should be noted, however, that while these

factors help assess the overall risk for early recurrence, theyare not taken into account when determining the treatment

strategy, as almost all tumors that show evidence of

endocrine responsiveness (i.e., the presence of any ER)

are considered candidates for endocrine therapy [17].

Recent evidence suggests that Ki67 labeling index (LI),

a measure of tumor proliferative capacity, could identify

patients at increased risk for poor outcomes within the St.

Gallen risk classification and Adjuvant! Online risk

categories [20]. Specifically, those with high Ki67 LI

(≥10%) had significantly poorer disease-free survival

(DFS) in both the intermediate (91.9% vs. 86.3%; P =

0.01) and high-risk groups (82.5% vs. 61.4%; P =0.01) of

St. Gallen 2007, compared with those with low Ki67 LI

[20].

The potential utility of gene expression profiles [21] in

the accurate prediction of risk recurrence and treatment

response is also being explored. The prognostic and

predictive value of the Oncotype DX recurrence score

assay using the 21-gene tumor signature has been validated

in ER+, N− patients receiving tamoxifen [22, 23]. The

phase 3 Trial Assigning Individualized Options for Treat-

ment was designed to determine the best individualized

treatment for PMW with ER+, N− breast cancer, with a

recurrence score of 11 – 25 [24]. The value of the Oncotype

DX recurrence score has been recently investigated in

major clinical trials of AIs. Recent results of the Trans

Arimidex, Tamoxifen Alone or in Combination (ATAC)

trial indicate that Oncotype DX is an independent predictor

of risk of DM in N− and N+, HR+ patients; however, the

data were not predictive of a differential benefit between

anastrozole and tamoxifen [25]. A prospectively controlled

study of 6,000 women with N− breast cancer (microarray in

node-negative and one to three positive-lymph node-diseaseFig. 1 Prevalence of distant metastases at 2-year peak of overall

recurrences [4]

582 Cancer Metastasis Rev (2010) 29:581 – 594



may avoid chemotherapy) compares a 70-gene expression

signature (Mammaprint) with common clinical – pathologi-

cal criteria to select patients for adjuvant chemotherapy

[26].

Thus, although several clinical and molecular prognostic

factors for early risk of DM are known, the ability to

accurately predict a favorable response to a particular

adjuvant therapy remains elusive. Advanced methods of individual risk assessment must be rigorously validated

before treatment strategies can be tailored to a patient ’s

unique molecular profile. Until then, all PMW with HR+

EBC should be considered at risk for recurrence and

candidates for adjuvant endocrine therapy, to minimize the

risk of DM and improve the chances of survival [17].

3 Adjuvant tamoxifen therapy and impact on DM

Until recently, on the basis of previous clinical trial results

[27], 5 years of tamoxifen was the standard adjuvant treatment for PMW with HR+ EBC. Meta-analysis of the

Early Breast Cancer Trialists’ Collaborative Group

(EBCTCG) showed that, at a median follow-up of 15 years,

5 years of adjuvant tamoxifen therapy significantly reduced

recurrence risk by 41% and mortality by 34% in patients

with ER+ tumors compared with placebo. Adjuvant

tamoxifen therapy reduced the risk of local recurrences by

53% (hazard ratio (HR)=0.47; P <0.00001) and the risk of

DM by 36% (HR= 0.64; P <0.00001) [27, 28]. Despite

these findings, many patients receiving tamoxifen continue

to experience recurrences, 50% of which occur within the

first 2 to 3 years after surgery, a period when DMs comprise

between 50% and 75% of recurrences [3, 4, 6].

Trials such as the National Surgical Adjuvant Breast and

Bowel Project (NSABP) B-14 study and the Stockholm

Tamoxifen trial indicate that tamoxifen therapy reduces the

risk of recurrence, but primarily for locoregional recurren-

ces and not the more serious and life-threatening DM [29,

30]. Also, recent studies have demonstrated that PMW with

ER+ EBC who are homozygous for variant alleles of

cytochrome P (CYP) 2D6 are unable to metabolize

tamoxifen effectively [31, 32]. Consistently, women receiv-

ing tamoxifen in combination with a CYP2D6 inhibitor

display an increased risk for breast cancer recurrence

compared with those receiving tamoxifen alone (2-year

recurrence 13.9% vs. 7.5%; HR=1.92; P <0.001) [33].

These findings led the Food and Drug Administration to

recommend relabeling tamoxifen to reflect the possible

negative effects on outcomes in women may have reduced

CYP2D6 activity. In addition, because of its estrogen-

agonistic activity in selected tissues, tamoxifen is associated

with serious adverse events (SAEs) such as endometrial

cancer and thromboembolic events [34].

4 AIs and treatment strategy trials

Third-generation AIs include anastrozole, letrozole, and

exemestane. Anastrozole and letrozole are nonsteroidal

drugs that block estrogen synthesis through a competitive

inhibition of aromatase, while exemestane is a steroidal AI

that blocks estrogen synthesis by irreversibly binding with

aromatase and inhibiting its activity [35]. All three AIsalmost completely block estrogen synthesis and have been

approved by the Food and Drug Administration for the

treatment of early-stage breast cancer because of their

efficacy and tolerability in a variety of clinical settings [36].

However, there is evidence that letrozole provides a greater

suppression of both plasma (residual estradiol (after 6 weeks

of AI therapy): 4.8% letrozole vs. 7.2% anastrozole, P =

0.018; residual estrone: 1.2% letrozole vs. 3.7% anastro-

zole, P =0.003; residual estrone sulfate: 1.1% letrozole vs.

4.7% anastrozole, P =0.003) and tissue (residual estradiol

(after 16 weeks of AI therapy): 2.4% letrozole vs. 11.0%

anastrozole, P =not reported (NR); residual estrone: 9.3%letrozole vs. 16.6% anastrozole, P =NR; residual estrone

sulfate: 9.9% letrozole vs. 27.1% anastrozole, P =NR)

estrogen levels compared with anastrozole [37]. Clinical

trials of adjuvant AIs in PMW with HR+ breast cancer

include initial adjuvant, extended adjuvant, switch, and

sequential trials (Fig. 2).

Upfront adjuvant trials — the ATAC trial, BIG 1-98

(monotherapy arms), and tamoxifen exemestane adjuvant

multicenter (TEAM) trials — randomized newly diagnosed

patients immediately following surgery and administered

5 years of treatment with either tamoxifen, an AI, or a

sequence of tamoxifen and AI [11, 12, 15, 16, 38, 39]. The

TEAM trial was designed to compare tamoxifen with the

Fig. 2 Types of adjuvant trials. AI aromatase inhibitor

Cancer Metastasis Rev (2010) 29:581 – 594 583



AI exemestane only at 2.75 years (first primary endpoint)

[39]; the trial was amended to compare exemestane with

sequential use of tamoxifen to exemestane at 5 years

(second primary endpoint) [40].

Switch adjuvant AI trials, such as the Intergroup

Exemestane Study (IES), Italian Tamoxifen Anastrozole

(ITA) trial, the Austrian Breast and Colorectal Study Group

8 (ABCSG 8), and ARimidex NOlvadex (ARNO) 95 trialsrandomized disease-free patients who received 2 to 3 years

of adjuvant therapy with tamoxifen as part of a 5-year

course and compared the relative efficacy of continuing

their treatment with tamoxifen or switching to an AI [14,

41 – 43]. Only patients who are disease-free at the time of

randomization are allowed to continue in switch trials,

excluding patients whose disease recurs during the first 2 to

3 years of tamoxifen therapy. This is different from

sequential adjuvant trials (BIG 1-98 sequential arms and

TEAM), which include all recurrences after randomization

in their efficacy analysis, including events during the early

peak at 2 to 3 years [2, 4]. Thus, while sequential trials aredesigned to assess the benefit of sequential therapy versus

monotherapy in newly diagnosed patients, switch trials

primarily address whether the risk of an event beyond

2 years is reduced by switching to an AI.

Lastly, extended adjuvant trials, such as the National

Cancer Institute of Canada MA.17 Trial, ABCSG 6, and the

NSABP B-33 trial, are designed to evaluate the benefit of

additional endocrine therapy by randomizing patients who

have already received a standard 5-year course of tamoxifen

to further treatment with an AI or placebo (or no treatment

in the case of the open-label ABCSG-6A trial) [44 – 47]. The

different strategies that have been examined (Fig. 2) across

multiple AI trials thus provide a number of treatment

options for endocrine therapy in PMW with EBC.

5 Upfront AI therapy and impact on DM

5.1 ATAC: upfront therapy with anastrozole

This was a large, double-blind, randomized, non-inferiority/

superiority comparison of anastrozole (n =3,125) with

tamoxifen (n=3,116) or a combination of anastrozole and

tamoxifen (n=3,125) for 5 years in PMW with EBC. The

combination arm was discontinued after the initial analysis

for lack of efficacy; thus, a third of the trial participants

were lost [12, 38]. Importantly, because the trial was

designed and implemented soon after the initial introduc-

tion of AIs as adjuvant therapy, the population was not

restricted to patients with HR+ disease [38] but also

included patients with HR-unknown tumors (16.3% of the

total trial population). Subsequent analyses have thus

focused on the comparison of anastrozole with tamoxifen

in both the intent-to-treat (ITT) population and the more

relevant subgroup of HR+ patients (n=5,216 of the original

9,366) [12, 15]. At a median follow-up of 33.3 months,

anastrozole demonstrated significantly better DFS com-

pared with tamoxifen (HR =0.87; P =0.005) and with the

combination of anastrozole and tamoxifen (HR=0.76;

P =0.002). Time to recurrence (TTR) was significantly

longer in the anastrozole group than in the tamoxifen group(HR=0.73, P =0.003), but there was no significant differ-

ence between tamoxifen and the combination groups (HR=

1.09; P =0.4). These initial results do not provide informa-

tion on DM rates and survival, because this was an event-

driven analysis requiring at least 704 distant recurrences,

and only 615 were recorded [38].

At a median of 68 months of follow-up, DFS was

significantly better with anastrozole versus tamoxifen in

HR+ p atien ts (HR= 0 . 83 ; P = 0 .0 05 ), a s w as T TR

(HR=0.74; P =0.0002), but time to distant recurrence

(T TDR) wa s n o t s ig nifica n tly d iffe ren t b e twe e n

anastrozole- and tamoxifen-treated groups in the HR+ population (HR=0.84; P =0.06; Table 1) [12]. Findings at

the 100-month follow-up also demonstrated that anastro-

zole was superior to tamoxifen in improving DFS (HR=

0.85; P =0.003) and TTR (HR =0.76; P =0.0001), with a

particular benefit in locoregional and contralateral breast

cancer recurrence. At this follow-up post treatment, there

were 16% fewer DM in the HR+ population (HR=0.84; P =

0.022; 305 anastrozole vs. 357 tamoxifen events) [15].

However, it is important to note that significant improve-

ment in TTDR was achieved post-treatment only after a

median follow-up of 100 months [15].

Disappointingly, while anastrozole appeared to provide

significant benefit with the improvement in DFS, no

improvement was seen in survival with more than 9 years

of follow-up. OS (HR=0.97; P =0.7; 472 anastrozole vs.

477 tamoxifen deaths), deaths after recurrence (HR=0.90;

P =0.2; 245 anastrozole vs. 269 tamoxifen deaths), and

deaths without recurrence (HR=1.05; P =0.6; 227 anastro-

zole vs. 208 tamoxifen deaths) were not significantly

different between the two groups [15]. A retrospective

analysis of ATAC at 2.5 years, undertaken to better

understand the types of early recurrences in the ITT

population, indicated fewer locoregional, DM, and contra-

lateral recurrences with anastrozole compared with tamox-

ifen, but the greatest benefit with anastrozole was in

reducing the risk of locoregional and contralateral events

with less impact on DM (7% reduction; Fig. 3) [3]. A

recently reported retrospective analysis of events at 2 years

in the HR+ population of ATAC also reported fewer overall

recurrences with anastrozole relative to tamoxifen, but the

reduction in DM was not significant (HR=0.79; 95% CI,

0.58 – 1.07) [48]. The AEs profile of ATAC displayed a

greater incidence of fractures (11% anastrozole vs. 7.7%




tamoxifen; P <0.0001) and arthralgia (35.6% anastrozolevs. 29.4% tamoxifen; P <0.0001) in anastrozole-treated

women in contrast to a greater incidence of endometrial

cancer (0.2% anastrozole vs. 0.8% tamoxifen; P =0.02),

venous thromboembolic events (2.8% anastrozole vs. 4.5%

tamoxifen; P =0.0004), and gynecologic abnormalities (i.e.,

vaginal bleeding, discharge, hot flushes; all P <0.0001) in

tamoxifen-treated women [12].

5.2 BIG 1-98: upfront therapy with letrozole

This large, double-blind, randomized, superiority trial was

designed and implemented by the IBCSG to evaluate the

efficacy of letrozole versus tamoxifen monotherapy, or

letrozole and tamoxifen as sequential therapy, in either

order, compared with letrozole alone as initial adjuvant

endocrine therapy, in PMW with EBC ( N =8,010). BIG 1-

98 was comprised of a four-arm option which assigned

patients to 5 years of letrozole (n =1,546); 5 years of

tamoxifen (n =1,548); 3 years of tamoxifen after 2 years of

letrozole (n=1,540); and 3 years of letrozole after 2 years of

tamoxifen (n =1,548), and a two-arm option, which

assigned patients to 5 years of letrozole (n =917) or

tamoxifen (n=911) therapy [11].

The BIG 1-98 trial is uniquely designed to study two key

questions regarding the use of AIs and tamoxifen: 1) the

efficacy of letrozole monotherapy versus tamoxifen mono-

therapy [11, 16, 49] and 2) whether sequential therapy, in

either order, is superior to monotherapy [16]. Unlike the

ATAC trial, BIG 1-98 required patients’ tumors to be HR+,

defined as positive for ER, PgR, or both [11]. The first

report from BIG 1-98 ( N =8,010), the primary core analysis

(PCA), was designed to compare letrozole and tamoxifen as

initial adjuvant therapy. The PCA included events from the

Initial adjuvant trials Endpoint F/U (months) HR for recurrence P value

BIG 1-98 (letrozole) TTDR 25.8 (PCA) 0.73a 0.001

76 (MAA) 0.85a 0.05

DFS 25.8 (PCA) 0.81a 0.003

76 (MAA) 0.88a 0.03

OS 25.8 (PCA) 0.86a 0.16

76 (MAA) 0.87a

0.08

ATAC (anastrozole) TTR 68 0.74 b 0.0002

100 0.76 b 0.0001

TTDR 68 0.84 b 0.06

100 0.84 b 0.022

DFS 68 0.83 b 0.01

100 0.85 b 0.003

OS 68 0.97 b 0.7

100 0.97 b 0.7

Table 1 Efficacy end points

from upfront adjuvant trials

comparing tamoxifen and

aromatase inhibitors

Source: [11, 12, 15, 16]

ATAC arimidex, tamoxifen

alone or in combination, BIG

Breast International Group,

DFS disease-free survival, HR

hazard ratio, OS overall

survival, MAA monotherapy

arm analysis, PCA primary

core analysis, TTDR

time to distant recurrence,

TTR time to recurrencea

ITT population b

HR+ population

236

143

196

133

0

90

180

270

N u m b e r o f r e c u r r e n c e s

17%

7%

TAM ANA TAM ANA

Overall Distant

a

168

125117

87

0

60

120

180

30%

30%

TAM LET TAM LET

Overall Distant

b

N u m b e r o f r e c u r r e n c e s

Fig. 3 Absolute reduction in overall recurrences and distant metas-

tases in the a Arimidex, Tamoxifen Alone, or Combination trial

(hormone receptor-positive patients) at 2.5 years [3] and b Breast

International Group 1-98 at 2 years [6]. ANA anastrozole; LET

letrozole; TAM tamoxifen




four- and two-arm option, including events from the initial

treatment period of the two sequential arms up to 30 days

after the switch, thus increasing the statistical power of the

comparison (Fig. 4).

At a median follow-up of 25.8 months, the PCA

demonstrated that letrozole treatment significantly improved

DFS (HR=0.81; P =0.003; 351 letrozole vs. 428 tamoxifen

events) and TTR (HR=0.72; P <0.001) and produced a significant 27% reduction in the risk of DM (TTDR)

compared with tamoxifen (HR= 0.73; P =0.001; 184

letrozole vs. 249 tamoxifen events). OS did not reach

statistical significance at this early follow-up (HR=0.86;

P =0.16; 166 letrozole vs. 192 tamoxifen events; Table 1)

[11]. A retrospective analysis examining the predictors of

early relapse in BIG 1-98 ( N =7,707) at 2 years found that

letrozole reduced the risk of both overall recurrence and DM

(87 letrozole vs. 125 tamoxifen events) by 30% (Fig. 3) [6].

This is particularly important given the preponderance of

DM at this time point [4] and the impact of DM on survival

[5, 8]. Based on the 2005 PCA results and the superiority of letrozole over tamoxifen, the IBCSG decided to unblind

the tamoxifen monotherapy arm and allow patients to cross

over to the letrozole arm. The other three arms remained

blinded [16].

Upon being counseled regarding the superiority of

letrozole versus tamoxifen, 619 patients (25.2%) on

tamoxifen monotherapy chose to cross over to letrozole;

most did so in 3 – 5 years and received letrozole for a

median of 18 months. Subsequent analyses of the PCA

(60.5 months), and the analysis of the monotherapy arms

(MAA) at 76 months, were affected by this crossover of

patients who were at high risk for recurrence, most likely in

favor of those in the tamoxifen arm, who benefited by the

early switch to letrozole. Therefore, data were presented as

protocol-defined ITT population (including crossover

patients) and a second analysis that censored patients at

the time of crossover. At a median follow-up of 76 months,

an analysis of the ITT population in the MAA demonstrated

consistent benefit, with a significant improvement in DFS

(HR=0.88; 95% CI, 0.78 – 0.99; P =0.03) and TTDR (HR=

0.85; 95% CI, 0.72 – 1.00; P =0.05) with letrozole [16].

Letrozole also demonstrated a strong trend, despite thecrossover, for improved OS (303 letrozole vs. 343

tamoxifen events; HR=0.87; 95% CI, 0.75 – 1.02; P =

0.08). In the censored analysis, results demonstrated even

greater benefit with letrozole. Patients receiving letrozole

had significant improvements in DFS (HR=0.84; 95% CI,

0.74 – 0.95), TTDR (HR=0.81; 95% CI, 0.68 – 0.96), and OS

(HR=0.81; 95% CI, 0.69 – 0.94).

There were 40 fewer deaths in the letrozole groups

compared with the tamoxifen group (303 vs. 343) and an

identical number of non-breast cancer-related deaths in each

group (87 vs. 87), indicating that the OS benefit provided

by letrozole is due to improved cancer survival. Consistent with the findings of the MAA at 76 months’ median follow-

up, the 60.5 months’ median follow-up of the ITT

population in the PCA also found a benefit in DFS (HR=

0.86; 95% CI, 0.77 – 0.96; P =0.008), TTR (HR=0.82; 95%

CI, 0.71 – 0.95; P =0.004), and TTDR (HR=0.79; 95% CI,

0.68 – 0.92; P =0.003). There was also a trend toward

improved OS with letrozole (HR= 0.87; 95% CI, 0.75 –

1.01; P =0.07) [49]. In the censored analysis, patients

receiving letrozole demonstrated significant benefits in

DFS (HR=0.83; 95% CI, 0.74 – 0.93), TTR (HR= 0.79;

95% CI, 0.68 – 0.90), and TTDR (HR=0.78; 95% CI, 0.67 –

0.92). Importantly, there was a significant benefit in OS

(HR=0.81; 95% CI, 0.70 – 0.94) [49]. However, the IBCSG

concluded that early crossover to letrozole, although ethical

F ig . 4 Breast International

Group 1-98 schema/analysis.

CT chemotherapy; ITT intent-to-

treat




and appropriate because of the significant survival benefit,

likely biased the ITT analysis in favor of tamoxifen and the

censored analysis in favor of letrozole, and makes accurate

assessments of OS difficult. Therefore, to adjust for the

potential bias due to crossover, an additional Inverse

Probability of Censoring Weighted (IPCW) analysis [50]

was undertaken to provide a more accurate estimate of the

clinical benefit of letrozole. The results of the analysis not only underscored the importance of validated methods,

such as the IPCW analysis, but also unequivocally

demonstrated that 5 years of letrozole significantly

improved DFS by 15% (HR= 0.85; 95% CI, 0.76 – 0.96)

and OS by 17% (HR=0.83; 95% CI, 0.7 – 0.97) [51], and

reflected the statistics that might have been observed in the

absence of selective crossover [16].

The 60.5-month update of the PCA population corrob-

orates findings of the 76-month monotherapy analysis

showing an emergent benefit of letrozole on survival with

long-term follow-up [16]. The survival benefit with

letrozole, not evident when anastrozole was compared withtamoxifen in the ATAC trial, underscores the substantial

benefit realized when early DM are controlled, as illustrated

by the PCA and the retrospective analysis examining the

predictors of early relapse at 2 years [6, 11]. This is the first

time an upfront adjuvant trial has demonstrated improve-

ment in OS, and it provides further evidence that preventing

early DM translates into a long-term survival advantage.

Findings from the safety analysis reported with the 60.5-

month update of the PCA population were consistent with

those of the initial PCA analysis, and with known AEs of

letrozole and tamoxifen, without evidence of risk increasing

over time [49].

5.3 FACE: upfront therapy — letrozole versus anastrozole

The randomized, open-label Femara Anastrazole Clinical

Evaluation (FACE) trial was designed to compare the safety

and efficacy of anastrozole versus letrozole in the upfront

AI treatment of PMW with HR+ and N+ breast cancer [52,

53]. The primary outcome measures are rate of DFS at

5 years between letrozole and anastrozole; secondary

outcome measures include safety, efficacy, OS, and time

to DM [52, 53]. Although results from the ATAC and BIG

1-98 trials allow for indirect comparisons, forthcoming

results from FACE should determine conclusively whether

any important efficacy differences exist between these two

nonsteroidal AIs.

5.4 TEAM: upfront therapy with exemestane

In this randomized, multinational, open-label study of

PMW with HR+ EBC ( N =9,300), investigators in nine

countries followed nearly identical protocols, with minor

differences based on local guidelines [54]. The trial was

originally designed to evaluate the efficacy and safety of

5 years of initial monotherapy with exemestane or

tamoxifen. However, based on the initial results of the

IES [41], the design was amended; women randomized to

tamoxifen had to switch after 2.5 – 3 years to exemestane for

the remainder of the 5 years. Therefore, the final design

compared exemestane monotherapy with sequential tamox-ifen to exemestane therapy for 5 years and compared

exemestane monotherapy with tamoxifen monotherapy at

2.75 years. At 2.75 years, there was no statistically

significant difference in DFS with tamoxifen versus

exemestane monotherapy (HR= 0.89; P =0.12), although

improvement in the secondary endpoint of time to DM was

observed (HR=0.81; P <0.03) [39]. As this was time-driven

rather than an event-driven analysis, the primary efficacy

results may have been affected by the high rates of

discontinuation while on tamoxifen monotherapy and the

timing of the exemestane switch [39]. The analysis is

complicated by the fact that almost 30% and 20% of patients randomized to tamoxifen and exemestane, respec-

tively, discontinued their assigned drug before a protocol-

amended crossover of all participants at 2.75 years.

6 Switch and sequence AI therapy

6.1 Switch study design

In this study design, patients who have already received

between 2 and 3 years of tamoxifen and have remained

disease-free are randomized to either continue tamoxifen or

switch to an AI. The population differs from that of an

initial adjuvant trial such as ATAC or BIG 1-98, which

randomizes patients at the time of surgery. Because patients

have already shown a favorable response to endocrine

therapy, they may be expected to have a better prognosis. In

addition, by definition, the switch design excludes patients

whose disease recurs early (i.e., within 2 years) while on

tamoxifen, including those at risk for early DM [4]. The

IES examined a switch to exemestane [14, 41], whereas the

ARNO 95, ITA, and ABCSG 8 studies examined a switch

to anastrozole versus continued tamoxifen [43, 55].

Combined results of smaller trials (i.e., ARNO 95/ABCSG

8/ITA) as well as the larger IES results are outlined below.

6.2 IES: switching from tamoxifen to exemestane

In this double-blind study, patients ( N =4,742) with ER+ or

ER-unknown breast cancer who tolerated 2 to 3 years of

tamoxifen without relapse were randomized to either switch

to exemestane or continue with tamoxifen for the remainder

of 5 years [14, 41]. The study thus excluded patients who




relapsed during prior tamoxifen treatment and selects for

patients at less risk of relapse or who are more sensitive to

hormonal therapy. Since patients had ER+ or unknown

disease, the ITT analysis includes patients who were later

found to have ER − disease. The population differs from

that of BIG 1-98, which included HR+ patients as defined

by positivity for ER, PgR, or both [11, 14].

At a follow-up of 55.7 months, in the most clinicallyrelevant ER+/unknown group, there was a significant

improvement in DFS among patients who switched to

exemestane (HR= 0.75; P =0.0001) compared with those

who remained on tamoxifen. The risk of DM (TTDR) was

also significantly reduced in exemestane-treated patients in

the ER+/unknown group (HR=0.83; P =0.03). There were

210 deaths in the exemestane group, versus 251 in the

tamoxifen group (17% relative reduction; P =0.05) [14].

Following adjustment for hormone receptor status, there was

a significant OS benefit in the ER+/unknown group [14]. In

the ITT population, 39 deaths were prevented by switching

to exemestane, with 15 fewer deaths related to breast cancer (151 exemestane vs. 166 tamoxifen) [14]. Similarly, an

updated survival and safety analysis at a median of

91 months of follow-up when at least 91% of surviving

patients had a minimum of 6 years follow-up available

demonstrated continuing improvement in OS with 352

deaths occurring in the exemestane group compared with

405 deaths in the tamoxifen group (HR=0.86; P =0.04) [56].

6.3 ABCSG 8/ARNO 95/ITA

A combined analysis of the similarly designed ABCSG

8 and ARNO 95 trials at 28 months of follow-up reported a

significant benefit in event-free survival (EFS; HR=0.60; P

=0.0009) and in DM-free survival (HR=0.61; P =0.0067)

for patients who switched to anastrozole after 2 years on

tamoxifen relative to those who continued on tamoxifen

[42]. However, there was no significant benefit in OS (97%

switch to anastrozole vs. 96% tamoxifen alone; P =0.16)

[42]. Similarly, a meta-analysis of ABCSG 8, ARNO 95,

and ITA showed significant improvement in DFS (HR=

0.59; P <0.0001), EFS (HR =0.55; P <0.0001), DM-free

survival (HR=0.61; P =0.002), and OS (HR=0.71; P =0.04)

[57], although differences in trial designs and patient

populations warrant a cautious interpretation of results.

The individual results of ARNO 95 (for DFS, HR=0.66; P

=0.049) [55], ABCSG 8 (for EFS, HR=0.68; P =0.02) [58],

and ITA (for DFS, HR=0.35; P =0.001) also support a

switch to anastrozole following 2 years of prior tamoxifen.

Again, although these trials show a significant DFS benefit

in switching patients from tamoxifen to anastrozole or

exemestane, it is not possible to directly compare outcomes

of upfront or switch trials because of differences in the trial

designs and populations analyzed.

6.4 ABCSG 8 trial: sequential therapy with tamoxifen

to anastrozole

This open-label trial examined the efficacy of initial tamox-

ifen therapy followed by a switch to anastrozole after 2 years

compared with tamoxifen monotherapy in patients with

hormone-sensitive breast cancer [42]. ABCSG 8 differed

from other sequential trials in that it randomized newlydiagnosed patients rather than randomizing at the point of

switch [58], allowing a more appropriate analysis of all

events from the time of randomization and not just from the

time of the switch. Notably, when including all events from

randomization at a median of 55 months, the reduction in

risk of recurrence (HR=0.76; P =0.07) achieved by switch-

ing to anastrozole was not significant [59]. In an updated

analysis (median 72 months) for relapse-free survival (RFS)

in the sequence sample ( N =2,922), there was a 21%

improvement with the switch to anastrozole (HR=0.79; P =

0.038) [59]. While these data, like the IES data, support the

contention that switching to an AI after 2 years is superior tocontinuing tamoxifen, the trial is limited by its open-label

design, and the updated results are complicated by crossover

of patients from tamoxifen to anastrozole ( N =82) and

withdrawals during the tamoxifen therapy period. Further-

more, while primary endpoints for the 55-month analysis

looked at EFS but not death from other causes, the 72-month

analysis included both RFS and death from other causes,

making a putative benefit difficult to extrapolate [59]. It is

also noteworthy that although the trial population was at low

to intermediate risk with ductal G1/2 and lobular tumors and

no chemotherapy [59], the 10-year cumulative incidence of

death in the tamoxifen arm was 20%, similar to outcomes in

the tamoxifen arm of other AI trials in a higher-risk patient

population.

6.5 BIG 1-98: STA

Based on the early data, the design of BIG 1-98 was modified

early during the course of enrollment to allow for five

additional pairwise comparisons, with analyses commencing

at randomization [16]. The design was amended to address

the clinically relevant question of sequential therapy, and

although not a protocol-defined analysis, given the proven

superior efficacy of letrozole versus tamoxifen, two of the

pairwise comparisons were considered the most clinically

relevant and the focus of this analysis: sequential tamoxifen

to letrozole therapy versus letrozole monotherapy ( N =

3,094), and sequential letrozole to tamoxifen therapy versus

letrozole monotherapy ( N =3,086), with a median follow-up

of 71 months. It is important to distinguish the design of the

sequential therapy analysis (STA) from other trials, as it

allowed for the evaluation of sequential therapy versus

letrozole monotherapy in a double-blind manner, including




the use of an AI before tamoxifen, which had not been

previously investigated [16].

Results demonstrated that sequential therapy was not

superior to letrozole monotherapy. DFS (HR=1.05; 99%

CI, 0.84 – 1.32), OS (HR=1.13; 99% CI, 0.83 – 1.53), and

TTDR (HR=1.22; 99% CI, 0.88 – 1.69) favored letrozole

monotherapy over sequential therapy with tamoxifen then

letrozole. TTDR (HR=1.05; 99% CI, 0.75 – 1.47) favoredletrozole over letrozole followed by tamoxifen. Thus,

women who received sequential therapy in either order

were at greater risk for DM than those receiving mono-

therapy. Because BIG 1-98 was designed as superiority

trial, a lack of difference between groups cannot be inferred

as equivalence between treatments.

At 2 and 5 years, there were fewer breast cancer events in

the letrozole monotherapy group than in the tamoxifen to

letrozole group in both N+ patients (2 years: 4.7% vs. 7.9%;

5 years: 12.4% vs. 14.7%) and N− patients (2 years: 0.9% vs.

1.3%; 5 years: 3.5% vs. 4.9%). The number of breast cancer

events in the letrozole monotherapy group was similar to that in the letrozole to tamoxifen group in N+ patients (2 years:

3.9% vs. 4.7%; 5 years: 12.4% vs. 12.5%), but there were

fewer breast cancer events in the letrozole monotherapy group

in N− patients (2 years: 0.9% vs. 1.5%; 5 years: 3.5% vs.

3.9%) [16]. These results suggest that adjuvant endocrine

therapy should begin with letrozole, unless contraindicated.

In addition, patients initiated on tamoxifen may be safely

switched to letrozole, if indicated (e.g., for SAEs).

6.6 TEAM: STA

Recently, results for the second of two co-primary

endpoints of the TEAM trial comparison of sequential

therapy versus exemestane monotherapy were reported

[40]. At a median follow-up of 5.1 years, and with 60%

of patients having completed 5 years of treatment, there

was no difference in efficacy between 5 years of upfront

exemestane compared with the sequence of tamoxifen to

exemestane. In the ITT analysis, there was no statistical

difference between the two arms in either DFS (HR=0.97;

95% CI, 0.88 – 1.08; P =0.604), TTR (HR=0.94; 95% CI,

0.83 – 1.06; P =0.293), or OS (HR=1.00; 95% CI, 0.89 –

1.14; P =0.999). The investigators concluded that for PMW

with endocrine-sensitive early breast cancer, both

approaches are appropriate, and further translational

research in the trial population may identify patients who

could benefit more from one strategy over the other.

6.7 Effect on practice recommendations

In contrast to the 2007 St Gallen International Expert

Consensus, the 2009 panel preferred AIs as initial adjuvant

therapy, particularly in higher-risk patients [17]. In addition,

the IBCSG — base d on updated results of BIG 1-98

demonstrating superior OS with letrozole versus tamoxi-

fen — now recommends starting adjuvant endocrine therapy

with letrozole, especially in patients at higher risk for early

recurrence [60]. If required, patients can be switched to

tamoxifen, but only after letrozole treatment for the first

2 years [60].

7 Extended AI therapy

7.1 Extended study design

In the extended adjuvant trial design, patients who received

the full course of adjuvant tamoxifen for 5 years and

showed no relapses or AEs during tamoxifen treatment

were randomized to receive further treatment with an AI or

a placebo.

7.2 MA.17: Extended therapy with letrozole

This double-blind, randomized, placebo-controlled trial ex-

amined the efficacy of letrozole as extended adjuvant therapy

in PMW ( N =5,187) with HR+ or receptor status-unknown

disease after completing 4.5 – 6 years of upfront tamoxifen

[61]. At a median follow-up of 30 months, women treated

with letrozole had significantly better DFS (HR=0.58; P =

0.00004) and distant DFS (DDFS; HR=0.60; P =0.002) than

those treated with placebo. Although OS was not signifi-

cantly improved in the ITT population (HR=0.82; P =0.3),

OS was significantly better with letrozole in N+ patients

(HR=0.61; P =0.04) [44]. The highly significant DFS,

DDFS, and OS benefit led to unblinding of the trial

approximately 1 year earlier than planned, when 66% of

patients receiving placebo chose to switch to letrozole, while

34% elected no further treatment [62]. After a median

follow-up of 5.3 years, women who chose to switch to

letrozole demonstrated significant improvements in DFS

(HR=0.37; P <0.0001) and DDFS (HR=0.39; P =0.004)

compared with patients who chose to terminate treatment

[62]. Furthermore, examination of the outcomes of the trial

indicated that letrozole improves DFS and DDFS (61%

reduction in risk of metastasis) even when there has been a

substantial period of time (median, 2.8 years; range 1.1 –

7.1 years) since the discontinuation of prior adjuvant therapy

[62]. These findings demonstrate that women who have

completed 5 years of adjuvant tamoxifen can benefit from

continuing treatment with letrozole, even if some time has

elapsed since discontinuing tamoxifen.

Interestingly, recent data on a subset of women in MA.17

(n=889) who were premenopausal when initially diagnosed

demonstrated that extended adjuvant therapy with letrozole

is significantly more effective in improving DFS in women




who are premenopausal at the time of the primary diagnosis

( P =0.02) [63]. The benefit of letrozole was significantly

greater in premenopausal women (HR=0.25; 95% CI, 0.12 –

0.51) than in postmenopausal women (HR=0.69; 95% CI,

0.52 – 0.91). Women who are premenopausal at the time of

diagnosis but become postmenopausal anytime before or

during adjuvant tamoxifen therapy should therefore be

considered for extended adjuvant therapy with letrozole.

7.3 ABCSG 6a: extended therapy with anastrozole

This open-label, non-controlled trial examined extended

adjuvant therapy in 856 HR+ PMW. Patients who completed

either 5 years of tamoxifen, or tamoxifen plus aminoglutethi-

mide for 2 years followed by tamoxifen monotherapy for

3 years, were randomized to either an additional 3 years of

anastrozole or no further treatment [45]. At a median follow-

up of 62.3 months, the risk of recurrence (local, contralateral,

or distant) was significantly reduced (HR=0.62; P =0.031),

as was the risk of DM (HR=0.53; P =0.034), in patientstreated with anastrozole compared with those receiving no

treatment, but no benefit was observed in OS (HR=0.89; P =

0.57) [45]. Although limited by its open-label design, the

results support the use of an AI in patients with a full course

of prior tamoxifen treatment.

7.4 NSABP B-33: extended therapy with exemestane

In this trial, ER+ PMW completing 5 years of tamoxifen were

randomized to receive exemestane or placebo for a further

5 years [47]. When results from the MA.17 trial showed that

extended adjuvant therapy with letrozole after 5 years of

tamoxifen provided significant benefits, the B-33 trial was

closed prematurely, so that exemestane therapy could be

offered to patients receiving placebo. At the time of

unblinding, 1,598 patients had been randomly assigned;

72% in the exemestane group continued on exemestane, and

44% in the placebo group elected to receive exemestane. As

a result, the trial failed to reach its target accrual, and the

primary endpoint of the trial (DFS) did not reach signifi-

cance after a median follow-up of 30 months (relative risk

(RR)=0.68; P =0.07) [47]. A statistically significant im-

provement was only shown in the 4-year analysis RFS (96%

vs. 94%; RR= 0.44; P =004). PMW with HR+ EBC continue

to be at risk of relapse and mortality after 5 years on

tamoxifen [64].

8 Meta-analysis of breast cancer outcomes in adjuvant

trials of AIs versus tamoxifen

The Aromatase Inhibitor Overview Group (AIOG) was

founded in December 2003 by the principal investigators of

all major AI clinical trials. Working in collaboration with

the EBCTCG, the AIOG sought to analyze the results of

almost 40,000 patients participating in AI trials of different

treatment strategies.

8.1 Upfront and switch therapy trials

A meta-analysis of randomized trials of monotherapy andswitching strategies presented during the 2008 San

Antonio Breast Cancer Symposium (SABCS) [65] was

recently published by the AIOG [66]. Data from random-

ized clinical trials comparing AIs with tamoxifen either as

initial monotherapy (cohort 1: ATAC and BIG 1-98/

IBCSG 18-98 trials) or after 2 to 3 years of tamoxifen

(cohort 2: German Adjuvant Breast Cancer Group/ARNO,

IES/BIG 2 – 97, ITA, and ABCSG 8 trials) were submitted

to the EBCTCG and used in separate meta-analyses of the

two cohorts. Primary analyses involved only PMW with

ER+ tumors. Cohort 1 included 9,856 patients with a

mean follow-up of 5.8 years. At 5 years, AI therapy wasassociated with an absolute 2.9% (standard error (SE)=

0.7%) decrease in recurrence (9.6% for AI vs. 12.6% for

tamoxifen; 2 P <0.00001) and a nonsignificant absolute

1.1% (SE=0.5%) decrease in breast cancer mortality

(4.8% for AI vs. 5.9% for tamoxifen; 2 P =0.1). Cohort 2

included 9,015 patients with a mean follow-up of

3.9 years. At 3 years from switching treatment (approx-

imately 5 years after starting hormonal treatment), AI

therapy was associated with an absolute 3.1% (SE=0.6%)

decrease in recurrence (5.0% for AI vs. 8.1% for

tamoxifen since switch; 2 P <0.00001) and an absolute

0.7% (SE=0.3%) decrease in breast cancer mortality

(1.7% for AI vs. 2.4% for tamoxifen since switch; 2 P =

0.02). There was no apparent heterogeneity in the

proportional recurrence reduction with respect to age,

nodal status, tumor grade, or PgR, status and no indication

of an increase in non-breast cancer deaths with AIs in

either cohort. The absence of a statistically significant

difference in non-breast cancer death and overall mortality

in both cohorts was considered to be a possible indication

in favor of the overall safety of treatment with AIs. It was

concluded that AI-treated patients have statistically sig-

nificant improvements in RFS in both cohorts, and AIs

provide a significantly lower recurrence rate in both

upfront and switching strategies compared with tamoxifen

(23% and 40%, respectively). An OS benefit was only

seen in cohort 2 (patients who switched to AIs). The lack

of a significant difference in breast cancer mortality in

cohort 1 is probably time-dependent, and further follow-

up may be needed, given the experience with tamoxifen. It

is noteworthy that the above data cannot answer the

question whether the switching approach is better than the

upfront approach.




8.2 Extended therapy trials

A meta-analysis of extended AI therapy trials was presented

by the AIOG during the 2009 SABCS [67]. Included were

efficacy results from the MA.17, ABCSG 6a, NSABP B-33,

and Adjuvant post-Tamoxifen Exemestane versus Nothing

Applied (ATENA) trials. The ATENA trial was closed

prematurely — after only 448 of the planned 1,803 patientshad been enrolled — because of results of the MA.17 trial

[68]. Taken together, the extended AI therapy trials suggest

that continuing treatment with an AI after 5 years of

tamoxifen is better than no further treatment. However, this

has only been proven conclusively with letrozole [44 – 46, 62,

67]. The optimal duration of extended adjuvant therapy

remains undetermined.

9 Discussion

While the risk of recurrence may be greater for patients with N+ status, all patients with EBC are at risk for recurrence,

including those with N− tumors of high grade or large size [4,

19]. Prognostic factors such as high Ki67 expression may

also identify a subgroup of patients (including those with N−

disease) at high risk for relapse and poor outcome [20].

Preventing DM is critical to improving outcomes; they

represent the majority of EBC recurrence events, which peak

approximately 2 years after surgery [4], and are associated

with the poorest prognosis compared with locoregional and

contralateral recurrences [5, 8, 10]. Therapies that effectively

reduce the risk of early DM are, therefore, likely to improve

long-term outcomes, including OS.

Major clinical trials clearly demonstrate a benefit of AI

therapy over tamoxifen in multiple adjuvant treatment

settings. In the initial adjuvant setting, both anastrozole

and letrozole have proven superior to tamoxifen in

improving DFS, whereas results for exemestane in this

setting remain inconclusive. In addition, initial adjuvant

letrozole has been shown to significantly reduce early DM

[6, 11]. This was also shown with anastrozole, but to a

significantly lesser extent [3, 48]. The significant reduction

in the incidence of early DM may in part explain the

emergent OS benefit with letrozole over tamoxifen with

long-term follow-up [16, 49], whereas no improvement in

survival has been seen for anastrozole over tamoxifen with

long-term follow-up [15]. Letrozole appears to be more

potent than anastrozole in terms of inhibiting estrogen [37,

69]. However, whether this results in differences in clinical

efficacy, remains to be determined in the directly compar-

ative FACE trial.

Adjuvant AI trials including the IES, ABCSG 8, and

ARNO 95 show that switching to an AI (anastrozole or

exemestane) after 2 to 3 years of tamoxifen is better than

continuing tamoxifen. However, it is not possible to

compare results from these switch trials with upfront trials,

because the switch trials included only patients who were

disease-free at the time of randomization. Recently reported

results from the STA of BIG 1-98 further suggest that using

a sequence of tamoxifen and letrozole, in either order, is not

superior to using letrozole monotherapy upfront [16], which

has already been shown to be better than tamoxifenmonotherapy. Exemestane was not shown to be better than

sequential therapy with tamoxifen and exemestane, but

exemestane also was not shown to be better than tamoxifen

in the upfront setting during the first 2.75 crucial years of

treatment [40]. Lastly, extended adjuvant trials have

demonstrated that continuing adjuvant endocrine therapy

with an AI improves outcomes when compared with no

further treatment in patients who have received the full

course of prior tamoxifen, although this benefit has been

conclusively shown only with letrozole.

10 Conclusions

Recent clinical trials have demonstrated the superiority of

initial treatment with AIs instead of tamoxifen, with

letrozole providing the most reduction in DM (30%) and

having the greatest impact on reducing the risk of early DM

[6, 11]. As reported by the updated analyses of BIG 1-98,

this is translating into an OS benefit with longer follow-up

[16, 49, 51]. A statistically significant effect of anastrozole

on reducing DM was observed only after a longer follow-

up (i.e., after 100 months), well beyond the crucial period

during which patients are at the highest risk of DM [15].

The STA of BIG 1-98 has shown that sequential therapy

with tamoxifen and letrozole, in either order, is not superior

to initial adjuvant letrozole [16], and recently published St.

Gallen guidelines seem to recommend the use of an AI

upfront, particularly in patients at higher risk of early

relapse [17]. However, for patients unable to begin adjuvant

endocrine therapy with an AI, switch and extended

adjuvant trials demonstrate that at the least, adding an AI

at some point after tamoxifen can help reduce the risk of

recurrence and improve outcome. While efforts to stratify

patients into prognostic subgroups are ongoing, it remains

difficult to quantify the risk of recurrence for an individual

patient. Until risk assessment strategies are more conclusively

validated in clinical trials, all patients should be considered

candidates for upfront AI treatment to effectively minimize

early DM and improve survival.

Acknowledgments Financial support for medical editorial assis-

tance was provided by Novartis Pharmaceuticals. We thank Maria

Soushko, PhD, of Phase Five Communications Inc. for medical

editorial assistance with this manuscript.




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Minimise Early Relapse in Postmenopausal Hormone-sensitive Breast Cancer

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